IN NOVEMBER 2016, a team of scientists from the Medical Research Council in Gambia visited primary schools armed with hundreds of beige-colored nylon socks. Handing them out to children there aged five to 14, the researchers instructed them to wear the socks overnight, only taking them off if they were washing their feet for prayer. The next day they returned to collect the dirty laundry, sort it, and put it in the mail to a British charity that would spend the next four months using the material to train dogs to recognize an odor imperceptible to the human nose: the molecular signature of malaria.

Dogs possess a sense of smell many times more sensitive than even the most advanced man-made instrument. Just how powerful is a pupper schnoz? Powerful enough to detect substances at concentrations of one part per trillion—a single drop of liquid in 20 Olympic-size swimming pools. With training, dogs can sniff out bombs and drugs, pursue suspects, and find dead bodies. And more and more, they’re being used experimentally to detect human disease—cancer, diabetes, tuberculosis, and now, malaria—from smell alone.

On Monday, researchers presented these latest results at the American Society of Tropical Medicine and Hygiene annual meeting in New Orleans. In double-blind lab tests, two canines proved able to correctly pick out the scent of children infected with malaria parasites 70 percent of the time. While all the schoolchildren appeared healthy, blood tests administered on-site discovered that 30 children were actually carrying the disease. This work is just a proof of concept, but the hope is that one day biodetection dogs could be deployed at airports, ports of entry, or other border crossings, to prevent asymptomatic carriers of the parasite that causes malaria from bringing it back into areas where the disease has been eradicated.

The work was funded by a $100,000 grant from the Bill & Melinda Gates Foundation, which has made malaria a priority in recent years, even spearheading an ambitious effort to eradicate the disease with Crispr-edited mosquitoes. The World Health Organization warned in its latest malaria report that decades-long progress in fighting the disease has stalled and is in danger of reversing. Each year, it kills half a million people, mostly children.

“The next stage is to figure out how well the dogs can do under natural circumstances with real people,” said James Logan, Head of the department of disease control at the London School of Hygiene & Tropical Medicine, which collaborated on the research. If they prove adept enough, the dogs could become a routine, noninvasive screening tool. They could be especially useful during the dry months, when there are few mosquitoes and very little transmission of the disease, but the parasite is holed up in human hosts who don’t show any symptoms. “Finding those individuals is currently very difficult,” says Logan.

An entomologist by training, Logan spent the early years of his career trying to understand why some people are more attractive to mosquitoes than others. A few years ago, he began to wonder if, like other parasites that rely on multiple hosts to complete their life-cycle, malaria-causing Plasmodium had a way to make infected humans smell tastier to the winged blood-suckers. Through a series of experiments, his research group showed that indeed, people infected with the parasite put out a unique aroma that sent skeeters a’swarming. They identified a cocktail of volatile compounds that proved a potent potion for attracting mosquitoes.

Where this molecular homing beacon comes from is still a mystery. Logan posits three possibilities: the parasite could be producing it, the stress from having a parasite in the body could be inducing human cells to secrete it, or the infection changes the bacterial communities living on people’s skin, resulting in the signature scent. The next phase of their research involves trying to further understand the specifics, so they could one day develop a device that does the work of a dog’s nose, without the need for a pooper-scooper. And in the meantime, they plan to begin trials in the real world to see how the dogs do with people, not just socks.

So how do you train a dog to detect disease? Much the same way you’d train one to pick out a whiff of gunpowder or heroin. You start by teaching them a game of sniff-and-seek.

“Dogs have something called neophilia, which means they are attracted to new and interesting odors,” says Claire Guest, who runs Medical Detection Dogs, a ten-year-old charitable organization devoted to supporting research into canine biodetection work. In their facilities an hour outside of London, human trainers place a few drops of a standard training liquid into small glass jars. Those get clipped behind a metal grate attached to a standing arm, which are lined up one next to the other. The dogs are instructed to walk down the line, pausing to sniff each one. If they stop at the new smell a trainer croons, “That’s it, good dog.” Soon they learn that if they stop and sit pointing at the right jar, they’ll get a treat.

The dogs don’t live at the facilities—they reside with families in the area and come in each day for a few hours of work. So it can take a few months to learn the basic rules of the game. But once that’s done, you can transition them to other smells, like schoolkids’ socks. MDD trained three dogs to detect malaria; a spaniel named Freya, Sally, a Labrador, and Lexi, a Lab-Golden Retriever mix. They’re 3 of 38 dogs currently working at the organization. Others are learning how to sniff prostate cancer, colorectal cancer, diabetes, Parkinson’s, and in the newest trials, the bacteria that causes urinary tract infections. Each dog is only trained in one disease indication, but not because they couldn’t learn more than one. Their human handlers just wouldn’t know which was which. In theory you teach them to raise a right paw for malaria and left paw for diabetes, but that would likely introduce more error into the equation.

All of this work is deeply personal for Guest, whose father passed away from Parkinson’s a few years ago. In 2009, her own dog, Daisy, nudged her repeatedly in the chest, nosing out a lump that turned out to be breast cancer. But she’s most excited by some of the organization’s research. MDD is collaborating with a scientist in Mexico City who’s built a bioelectronic nose for the purposes of detecting cancer via odor. But its algorithms need to be taught how malignant tissues smell. That’s where the dogs come in. “We can say to the dog, ‘here’s 10 cancers, which smells the strongest,’ and then we feed that data to the AI,” says Guest. “If machines can understand what odor is, that will be a much more powerful tool for us in the future.”

A new study offers a potential explanation for why many patients with acute myeloid leukemia experience a relapse after a stem cell transplant, and suggests a therapeutic approach that may help them back into remission

Patients with AML, an aggressive cancer of the blood, often receive treatment in the form of stem cell transplantation, in which a compatible donor’s blood-forming cells are transplanted into a patient.

The donor’s immune cells then attack and kill the leukemia cells. But even if this treatment initially is successful, many patients experience a recurrence of the leukemia after transplantation that often proves fatal.

The study, which appears in the New England Journal of Medicine, involved the DNA sequencing of AML cells from 15 patients who relapsed after stem cell transplants and, as a comparison, 20 AML patients who relapsed after chemotherapy.

The researchers found that the mutations present in relapsed AML cells after transplantation were similar to those after chemotherapy.

But the researchers found a significant difference in the cells’ patterns of gene expression, that is which genes are active and to what degree. The cells from patients who relapsed after transplant often had greatly reduced expression of genes involved with the recognition of cancer cells by the immune system.

STEALTHY RETURN
In other words, when the cancer came back in these patients, it returned in a kind of stealth mode. These stealth leukemia cells lacked proteins that the donor’s T cells use to identify them. When the donor’s immune cells can no longer detect the leukemia cells, the T cells fail to destroy them.

The investigators also identified a natural signaling molecule—interferon gamma—that forced the stealth leukemia cells to reveal themselves again, presenting new therapeutic possibilities for AML patients who relapse in this way.

“We were surprised by these findings because we and others had previously studied samples of relapsed leukemia in every which way,” says senior author John F. DiPersio, professor of medicine in oncology and director of the oncology division at the School of Medicine at Washington University in St. Louis.

“But there’s a rational explanation, since the way stem cell transplants attack leukemia—through an immunologic mechanism—is going to favor the survival of cancer cells that become invisible to the immune system,” DiPersio says.

‘DIMMER SWITCH’
The researchers found that the relapsed cancer cells did not have recurring genetic mutations that caused them to go into stealth mode by disabling the genes that control immune recognition. Rather, the cells possessed something like a “dimmer switch,” dialing down the expression of immune markers. And dimmer switches, unlike mistakes in DNA, are often easier to adjust.

An immune signaling molecule called interferon gamma has long been known to dial up the body’s natural immune defenses. Indeed, interferon gamma is vital to the body’s response to infection, and is widely known for its ability to increase expression of the immune markers that these stealth cancer cells have hidden away.

“When we treated leukemia cells from patients’ relapse with interferon gamma, it turned back on those immune markers that had become invisible, suggesting that this process is reversible,” says co-first author Matthew J. Christopher, an assistant professor of medicine, who also treats patients at Siteman Cancer Center.

OTHER MUTATIONS?
The Food and Drug Administration has approved interferon gamma for treatment of a rare condition called chronic granulomatous disease, an inherited immune disorder that results in frequent and life-threatening bacterial or fungal infections.

The researchers are seeking to identify other small molecules that may have the same effect as interferon gamma, DiPersio says. In the 50 percent of patients who relapsed after transplant but whose cells did not go into stealth mode, the reason for relapse is not yet clear.

Further studies involving many more patients will be necessary to determine whether other DNA mutations, or alternative dimmer switch mechanisms, may be involved in relapsed AML.

Additional researchers from Washington University in St. Louis contributed to the research. The National Cancer Institute and the Foundation for Barnes-Jewish Hospital supported the work.

@SandiA,
If you rate your pain as a 4 or above then your heart rate and blood pressure will rise which then causes your GI tract to slow down so you metabolize the drugs at a slower rate. If you have Benadryl at home take some 15 minutes before you take your pain medicine. This will relax you, slow down your heart rate and speed up your GI tract to metabolize better. Best of luck to you.

You could ask your doctor for a referral to the Pain Clinic, and take a list of your questions about how the pain meds work, etc. They can also tell you about methods of pain control other than pain meds. Best wishes.

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